The adducts that form when aldehydes modify proteins have been implicated in the pathogenesis of vascular disease and aging. Our previous studies indicated that p-hydroxyphenylacetaldehyde (pHA), the major product of L-tyrosine oxidation by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes, covalently modifies the (-amino group of lysine residues at sites of inflammation. Here, we report that pHA also reacts with the amino group of synthetic phospholipids and red blood cell model systems. Fast atom bombardment mass spectrometric analysis of ethanolamine glycerophospholipid or serine glycerophospholipid incubated with pHA and NaCNBH3 detected covalent adducts that were consistent with reduced phospholipid Schiff base adducts. We confirmed the reaction of the aldehyde with the amino group through 1H NMR and mass spectrometric analysis of polar head groups recovered from the modified and reduced parent lipid. When we exposed phospholipid model systems and cell membranes to physiological levels of L-tyrosine and the myeloperoxidase-hydrogen peroxide-chloride system followed by treatment with NaCNBH3, we obtained reduced Schiff base adducts of pHA with ethanolamine glycerophospholipid and serine glycerophospholipid (pHA-PE and pHA-PS, respectively). The reaction required myeloperoxidase, hydrogen peroxide, L-tyrosine and chloride ion; it was inhibited by catalase or heme poisons, implicating a peroxidase in the pathway. Collectively, these results demonstrate that an aldehyde generated by the myeloperoxidase system of phagocytes can covalently modify the amino groups of ethanolamine glycerophospholipid and serine glycerophospholipid. Because amino glycerophospholipids are critical components of cell membranes and circulating lipoproteins such as LDL, similar reactions may play important roles in the initiation or progression of disease at sites of inflammation.